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  • Title: Analysis of hypoxia-inducible factor-1alpha accumulation and cell cycle in geldanamycin-treated human cervical carcinoma cells by laser scanning cytometry.
    Author: Schwock J, Geddie WR, Hedley DW.
    Journal: Cytometry A; 2005 Dec; 68(2):59-70. PubMed ID: 16228978.
    Abstract:
    BACKGROUND: Tumor hypoxia has been linked to increased disease aggressiveness and poorer treatment outcomes, and the transcription factor hypoxia-inducible factor-1 (HIF-1) has been identified as the key molecule mediating the cellular response to hypoxic microenvironments. The alpha-subunit of this factor is accumulated under hypoxia and rapidly degraded during re-oxygenation, rendering the reliable measurement of HIF-1alpha a difficult task. Heat shock protein 90 (Hsp90) is an essential protein that controls the activity, turnover, and trafficking of a variety of other proteins including HIF-1alpha and cell cycle regulators. Hsp90 inhibitors like geldanamycin therefore have the potential to target tumor-cell survival by at least two mechanisms, compromising the accumulation of HIF-1alpha and cell proliferation. METHODS: We describe here the simultaneous measurement of HIF-1alpha and cell cycle parameters by laser scanning cytometry (LSC) after exposure of two different human cervical carcinoma cell lines to hypoxia and geldanamycin. RESULTS: Our analysis demonstrates that the cell lines react to hypoxia and drug treatment in a distinct way, with SiHa being more affected by low oxygen concentrations than is ME180, which was more sensitive to geldanamycin treatment. Both cell lines respond to geldanamycin with a G(2)/M-phase arrest and a decrease in HIF-1alpha accumulation. Cell death due to geldanamycin occurs in association with mitosis, presumably through mitotic catastrophe. CONCLUSION: Our results indicate that LSC can significantly contribute to the evaluation of in vitro drug effects particularly with respect to tumor hypoxia and the measurement of HIF-1alpha.
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